CIRCULATING TUMOR CELLS IN MINIMALLY INVASIVE FOLLICULAR THYROID CARCINOMA AND BENIGN THYROID TUMORS WITH A FOLLICULAR PATTERN: PILOT EXPERIENCE.

PURPOSE: Minimally invasive follicular thyroid carcinomas (MIFCs) are uncommon; literature offers limited guidance on their natural history and management. Starting January 2015 we measured circulating tumor cells (CTCs) in patients with MIFC (n=22) or benign thyroid tumors with follicular features (n=4). METHODS: In a retrospective analysis, we assessed detectability of and serial changes in CTC, compared demographic/clinical differences between CTC-positive versus CTC-negative subgroups using Student's t-test, and examined correlations between CTC status and serum thyroglobulin using Spearman's test. CTCs were quantitated via immunomagnetic separation/microscopic inspection. RESULTS: Thirteen patients (50%: 12/22 MIFC, 1/4 benign tumor) were initially CTC-positive; 3 remained CTC-positive in ≥1 subsequent measurement. CTC-positive patients had larger tumors and more frequent multifocality and vascular invasion versus CTC-negative patients (n=13). However, no tested variable differed significantly between the subgroups. After 17.2±10.5 months, neither subgroup showed evidence of disease. Significant correlation was absent (p ≥ 0.263) between CTC and Tg negativity (r = 0.243; n=13 evaluable) or initial CTC positivity and Tg positivity (r = -0.418; n=9 evaluable). CONCLUSIONS: In the studied settings, CTC measurement is feasible, has unclear clinical/outcome implications, but may provide different information versus thyroglobulin testing. Lengthier assessment is warranted in larger series.

The colorectal cancer stem-like cell hypothesis: a pathologist's point of view.

Colorectal cancer is the fourth most common cancer in men and the third most common cancer in women worldwide. The partial failure of classic therapeutic options makes scientists to doubt the efficacy of systemic treatments in targeting the essential cell populations and achieving cure as a final goal. Overgrowing data suggest that cancer is a disease closely linked to stem cells (SCs). It is well known that the first identification of cancer stem-like cells in acute myeloid leukaemia was soon followed by similar results in solid malignancies, including colorectal cancer, and the classic model for colon carcinogenesis supports the development of sudden mutations that will lead to the activation or inactivation of certain oncogenes or tumor suppressors. Thus, this process may go on for years before the first symptoms and the only cells able to withstand for many years, avoid apoptosis and have a high regenerative capacity are the progenitor cells found at the lower part of colon crypts. A more profound study of the mechanisms and molecular signalling pathways that control the basic characteristics of SCs, such as asymmetrical division or self-renewal, may help comprehend the basic mechanisms of cancer genesis and progression. This will result in the development of new therapeutic agents that may target chemoresistant cell populations and improve the therapeutic results. In the current review we point out the importance of cancer stem-like cells in colorectal oncology from a pathologist's point of view, stating the obvious correlation between histology, embryology and surgical pathology.

Gastric metastasis of cervix uteri carcinoma, rare cause of lower gastric stenosis.

AIM: the paper presents a rare case of metachronous gastric metastasis of uterine cervix cancer, clinically manifested through severe pyloric stenosis. METHOD: 49-year-old patient, operated on in January 2009, with uterine cervix cancer (Squamous cell carcinoma T2bN1M0), is hospitalized in August 2011 with pyloric stenosis: epigastric pains, abundant, stasis, late postprandial emesis, significant weight loss, stomach form visible upon abdomen inspection. Endoscopy: antral stenosis with intact gastric mucosa, and CT-scan: circumferential intramural gastric tumor, stomach dilated in the upper part, lack of cleavage between the tumor and the liver bed of the gall bladder. CEA increased to 13,78 (below 5), CA 19-9 slightly increased 29.9 (below 27). The case is considered as a second neoplasia and a D2 subtotal gastrectomy was performed, with 1 positive ganglion out of 27 on block with atypical hepatectomy of segments 4-5 for liver invasion, the final mounting being Y Roux. RESULTS: The histopathological examination shows a gastric metastasis of squamous carcinoma, of uterine cervix origin, the invaded perigastric ganglion having the same aspect of uterine cervix carcinoma. The post-surgery evolution was favorable, under chemo radiotherapy the patient being alive without relapse at 9 months post-surgery. CONCLUSION: In the literature there are 2 more cases of gastric metastasis of uterine cervix carcinoma, and 4 of uterine carcinoma without topographic indication, but without the histological documentation of the tumor filiation, without data related to resecability or follow-up, the case at hand being, from this perspective, the first documented resectable metachronous gastric metastasis from a cervix uteri carcinoma.

[Immunohistochemical screening of hMLH1 and hMSH2 gene mutations in patients diagnosed with colorectal cancer and microsatellite instability suspicion]. / Screeningul imunohistochimic al mutatiilor genelor hMLH1 respectiv hMSH2 la pacientii diagnosticati cu cancere colorectale si suspiciune de instabilitate microsatelitara.

STUDY AIM: Immunohistochemical screening of hMLH1 and hMSH2 gene mutations in patients diagnosed with colorectal cancers, suspected of having microsatellite instability, as diagnosed between January 2002 and December 2009 in the Surgery Department of the CF Clinical Hospital Cluj-Napoca (prospective non-randomised study). METHODS: Inclusion criteria were adenocarcinoma pathology finding and also minimum one of the revised Bethesda criteria for genetic testing of microsatellite instability in colorectal cancers. 110 eligible patients were divided in 2 study groups according to the number of Bethesda criteria met (group A - 1 criteria; group B - 2 or more criteria). Both groups were statistically compared considering the clinical and pathological parameters specific to the Lynch syndrome. We performed immunohistochemical staining to determine the expression of hMLH1 and hMSH2 genes in the tumors of all the patients. RESULTS: We found the differences in age, colorectal family history and right colon tumor site between the two groups to be statistically significant. Immunohistochemical stainings showed lack of hMLH1 gene expresion in 9 patients and of hMSH2 gene in 4 patients respectively. CONCLUSIONS: Immunohistochemical staining can identify patients who need to be genetically tested for mutations of the DNA mismatch repair genes, in order to establish the correct diagnostic of Lynch syndrome.

Could serologic and ultrasonographic indexes be useful for therapeutic decisions in patients with ovarian cancer?

UNLABELLED: The objective of this study is to assess and quantify a relationship between different categories of prognostic factors in ovarian cancer, to establish patterns that explain the aggressiveness of some tumors, as well as to consider the above mentioned issues with regard to therapy decisions. MATERIAL AND METHODS: This prospective observational and analytical research comprised 124 cases. The following were calculated: descriptive statistics, statistical comparisons, linear and multiple regressions, survival calculations, for clinical, serological, ultrasonographic, biological and temporal variables. In addition, new prognostic indexes were introduced. RESULTS: A significant difference was found between well known predictors for evolution of ovarian cancer in the malignant and benign groups: Platelet Derived Endothelial Cell Growth Factor (PDECGF) p=0.0001; CA125 p=0.0027. Potential ultrasonographic and serologic predictors for malignity of ovarian masses were identified. Only two ultrasonographic predictors: Multilocular Solid Masses insight the tumor and Diastolic Notch fulfilled the required values in order to be considered independent predictors for disease free interval. High level correlation between serologic and ultrasonographic predictors was calculated; significant correlation between preoperative and postoperative vascular indexes was demonstrated. DISCUSSIONS: The results suggest the possibility of therapy in ovarian cancer patients adjusted also to the angiogenic component of the disease.

The history of the Laboratory of Pathology of the Cluj-Napoca Oncological Institute.

The Laboratory of Pathology of the actual "Professor Ion Chiricuta" Oncological Institute of Cluj-Napoca, former "Iuliu Maniu" Institute for Cancer Study and Prophylaxis, had the privilege that in its framework carry on an important part of their activity professors Titu Vasiliu and Rubin Popa, who are forming, beside Victor Babes, the golden trinity of the Romanian pathology. The Cancer Institute of Cluj, one of the first in the World, was founded in 1929, especially by the clear-sightedness and the efforts of Professor Iuliu Moldovan, the master of the modern Romanian school of hygiene. The clinic division was assisted by a Laboratory of Pathology, whose chief was appointed the young pathologist of high competence, Rubin Popa, associate Professor of this department of the Cluj School of Medicine. In 1942' he became director of the Institute, function accomplished until his premature disappearance in 1958. Titu Vasiliu worked in the Oncological Institute from 1949, a year after his forced retreat from the chair of pathology, up to 1958. Fortunately, his premature disappearance did not interrupt the activity of the laboratory, because the management of the Oncological Institute was committed to Ion Chiricuta, an experimented and modern surgeon of Bucharest. From 1960, the Laboratory of Pathology has been led by Professor Augustin Muresan, an experimented, rigorous and prudent pathologist, who has imprinted these indispensable qualities to his disciples learning under his leadership. The activity of the laboratory has been very favorably influenced by the presence of Professor Gheorghe Badenski from the Department of Microbiology. The collaboration with Professor Eugen Pora from Babes-Bolyai Department of Animal Physiology and his disciples, Virgil Toma, Draga Nestor, Sena Rosculet, Carmen Stugren and Georgette Buga has carried on the performance of interesting works concerning the thymus involution in tumor-bearing hosts and its signification for the depressed immunity in the advanced stages of cancer. In the same direction, the behavior of mast cells has been studied in collaboration with Professor George Csaba from the Budapest Medical University, Department of Biology. The observations brought about were remarked by the Canadian scientist Hans Selye. Most of these works have been included in the book "Immunity and cancer", distinguished with "Victor Babes" Prize of the Romanian Academy. The arrival in the Institute of Professor Ion Macavei, disciple of Iuliu Hatieganu and founder of the Clinical Hematology in Cluj, expert in blood and bone marrow cytology, has given a strong impulse to the studies of malignant hemopoietic diseases. The current use of cytologic and histopathologic examinations in this field of pathology and, especially, the introduction by him, for the first time in Romania, of the osteomedullary biopsy has permitted the elaboration of an appreciated work about the cytologic and histologic diagnosis of lymphadenopathies. In the histochemical-histoenzymatic period of the microscopic diagnosis, between the years 1960-1990, the laboratory has enjoyed by the advices and the material help of Professor Raymond Wegmann from the Paris University, Institute of Histochemistry, the founder-editor of the International Review of Histochemistry, from 1976, of Cellular and Molecular Biology, who visited our laboratory in 1992. From 1965, in an adjacent Laboratory of Cytogenetics, Corneliu D. Olinici has performed the first karyotypes in Cluj and has teached the method to several other specialists. Despite the technical difficulties, the works performed in the Laboratory of Pathology have succeeded sometimes to reach the quality required by Professor Chiricuta to a valuable scientific work in cancerology. This performance has been obtained by a study concerning Crabtree effect variations in tumoral metastases or about lactic-dehydrogenase behavior in breast carcinomas.

Report from the OECI Oncology Days 2014.

The 2014 OECI Oncology Days was held at the 'Prof. Dr. Ion Chiricuta' Oncology Institute in Cluj, Romania, from 12 to 13 June. The focus of this year's gathering was on developments in personalised medicine and other treatment advances which have made the cost of cancer care too high for many regions throughout Europe.

The axis of evil in the fight against cancer.

Over the past years medicine has undergone intensive changes, evolving from classical semiology and internal medicine to individualized treatments, based on recent breakthroughs in immunology and genetics. This concept has had a profound impact in all medical specialties and as a consequence pharmacology and various treatment plans will be based on monoclonal antibodies and targeted cell therapies. One such target is the SDF-1-CXCR4 axis bacause it plays a critical role in many physiological processes that involve cell migration and cell fate decisions, ranging from stem cell homing, angiogenesis and neuronal development to immune cell trafficking. The chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha are also implicated in various pathological conditions, including metastatic spread and HIV infection. In this review, we present the concept that the SDF-1-CXCR4 axis is a master regulator of trafficking of both normal and cancer stem cells, based on the growing evidence that it plays a pivotal role in the regulation of trafficking of normal hematopoietic stem cells and their homing to the bone marrow. Because most malignancies originate in the progenitor cell compartment, cancer stem cells also express CXCR4 on their surface and migrate to organs that highly express SDF-1. Hence, we postulate that the metastasis of cancer stem cells and trafficking of normal stem cells involve similar mechanisms, which may be regulated by several small molecules related to inflammation. Consequently, strategies aimed at modulating the SDF-1-CXCR4 axis could have important clinical applications in both tissue engineering and in clinical hematology and oncology to inhibit metastasis of cancer stem cells.

Pancreatic exocrine adult cells and placental stem cells co-culture. Working together is always the best way to go.

BACKGROUND AND AIM: The progress made in the last few years have managed to come up withy the possibility of using different stem cell types in an endeavor to correct the alterations that appear in different degenerative diseases. The pancreas, an organ with extremely low regenerative capacity, both for the endocrine and for the exocrine component, is an organ perfect for cell therapy in the hope of restoring its function and cure diabetes mellitus or chronic pancreatitis. One main issue in the stem cell transplantation problem is represented by the influence of the cellular niche, formed by completely differentiated cells, on the phenotype and function of the transplanted cells. In this study, we challenge current knowledge in the field by evaluating the influence of exocrine pancreatic cells on placental stem-like cells using the co-culture technique. METHODS: In our experiments, we used two different protocols in which adult pancreatic cells were cultured together with mesenchymal stem cells isolated from human placenta. In the case of the first protocol, we seeded pancreatic cells on a pre-adhered single-cell layer of mesenchymal stem cells and in the second one, the seeding of two cell populations in suspension was done at the same time, after passage. During the experiment, we evaluated the alteration of the morphology of the placental cells using and inverted phase microscope and reverse transcriptase-PCR. RESULTS AND CONCLUSIONS: Based on morphology, in both cases the interaction between epithelial pancreatic cells and placental ones have determined a change in phenotype from mesenchymal to epithelial-like. Taking into consideration the gene expression, placental stem cells have maintained pluripotency gene expression throughout the study. They also expressed pancreatic amylase. These experiments bring out the plasticity of placental stem cells, the cell microenvironment with a decisive part in phenotype and the level of gene expression. The results obtained in vitro can bring a new picture on the effects of the pancreatic stem cell niche.

Expression of VEGF, VEGFR, EGFR, COX-2 and MVD in cervical carcinoma, in relation with the response to radio-chemotherapy.

INTRODUCTION: Despite the improvement in the treatment results due to modern irradiation techniques and to the association of chemo-radiotherapy, cervical cancer remains an unsolved problem of oncology both due to the increased rate of local failures and of the distant metastasis. Efforts to implement new therapeutic strategies in order to obtain better results in patients with cervical cancer appear justified. Neovascularization is an important step in the tumor progression and the therapeutic targeting of the tumor blood vessels appears to be a good strategy to follow in the anti-cancer treatment. Thus, even in an incipient phase of the clinical research process, the combination between the anti-angiogenic aimed therapies and the current radio-chemotherapy seems to represent a new, feasible and promising approach. The aim of the present study was to determine the prognostic and/or predictive value of some biological markers of tumor angiogenesis and of their implication in increasing the efficacy of current treatments for this cancer. MATERIALS AND METHODS: So far, 54 women were included in a prospective trial: 44 having an advanced cervical carcinoma and 10 healthy women, as controls. A tumor biopsy and a blood sample were obtained from each patient before the start of therapy. The density of microvascularization was assessed using CD34 monoclonal antibody (hot spot technique), the expression of angiogenic factors VEGFR, EGFR and COX-2 were determined in tumor biopsies by specific immunohistochemistry techniques, using primary antibodies anti-EGFR, anti-VEGF and anti-COX-2 respectively. The quantitative polymerase chain reaction (Real Time PCR) was employed for assessing the expression level of the genes involved. Serum VEGF was determined by quantitative ELISA technique. RESULTS: Among the studied clinical and molecular factors, we found to be predictive for the type of response the following factors: tumor size at diagnosis (p=0.01), VEGFR2 expression (p=0.02) and a tendency to significance for patients' age (p=0.06). From the large panel of studied markers it was observed correlation between MVD expression with stromal COX-2 (p=0.01) and a tendency with epithelial COX-2 (p=0.06). Stromal COX-2 has higher correlation with VEGFR2 (p=0.01) and MVD (p=0.01) and also has a lower correlation with tumor size (p=0.08). CONCLUSIONS: Univariate analysis demonstrates that the response to radio-chemotherapy in cervical cancer is related to a set of clinical and molecular factors as: the tumor size, the expression of VEGFR2 as mRNA level and the patients' age. Unfortunately, the multivariate analysis by logistic model selects only VEGFR2 expression for prediction of tumor response. The interrelations between the different biomarkers demonstrate the complexity of the tumor progression process and the necessity of further studies to identify new therapeutic targets.

Stem-like cells in colorectal oncology.

Although the treatment for colorectal cancer has seen considerable progress during the past few years, the mortality associated with this type of tumor remains high. This article presents the existing methods of treatment, focusing on the new treatments made possible by the advances in the field of normal and tumor stem cells. Starting from the normal architecture of the colon and the properties of the cells identified in it, we sought to present a few notions concerning these cells which have a direct relevance for both pathology and treatment. The manner in which they divide (symmetrically or asymmetrically) as well as the molecules which control their circulation through the body are just a few examples which are likely to influence the treatment of colorectal cancer in the future.